Comparative Proteome Analysis of Mycobacterium tuberculosis Strains - H37Ra, H37Rv, CCDC5180, and CAS/NITR204: A Step Forward to Identify Novel Drug Targets

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Author(s): Shradheya R.R. Gupta, Ekta Gupta, Avnam Ohri, Sandeep Kumar Shrivastava, Sunita Kachhwaha, Vinay Sharma, Rupesh Kumar Mishra, Ravi Ranjan Kumar Niraj*.

Journal Name: Letters in Drug Design & Discovery

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Abstract:

Background: Mycobacterium tuberculosis is a causative agent of tuberculosis. It is a non-motile, acid-fast, obligatory aerobic bacterium. Finding novel drug targets in Mycobacterium tuberculosis became extremely important as the bacterium is evolving into more dangerous multi-drug resistant pathogen. The predominant strains in India belong to Central-Asian, East-African Indian, and Beijing clad. For the same reason, the whole proteomes of a non-virulent strain (H37Ra), a virulent (H37Rv) and two clinical strains, a Central-Asian clad (CAS/NITR204) and a Beijing clad (CCDC5180) has been selected for comparative study. Selecting a phylogenetically close and majorly studied non-virulent strain is helpful in removing the common and undesired proteins from the study.

Objective: The study compares whole proteome of non-virulent strain with the other three virulent strains to find unique protein responsible for virulence in virulent strain. It is expected that the drugs developed against identified targets will be specific to the virulent strains. Additionally, to assure minimal toxicity to the host, we also screened the human proteome.

Methods: Comparative proteome analysis was used for target identification and In-silico validation of identified target protein Rv2466c, identification of respective ligand of identified target protein and binding interaction study using Molecular docking and Molecular Dynamic Simulation study were used in this study.

Results: Finally, eleven proteins found to be unique in virulent strain only and out of which Rv2466c (PDBID: 4ZIL) was found as an essential protein and identify as a putative drug target protein for further study. The compound glutathione found to be the suitable inhibitor for Rv2466c. In this study we used comparative proteomics approach to identify novel target protein.

Conclusion: This study is unique as we are quite assured that the study will move forward the research in a new and effectual direction to cure the deadly disease (tuberculosis) caused by Mycobacterium tuberculosis. Rv2466c identified as novel drug target and glutathione as respective ligand of Rv2466c. Discovery of novel drug target as well as drug will provide solution to drug resistance as well as infection caused by Mycobacterium tuberculosis.

Keywords: Multi-drug resistance, Mycobacterium tuberculosis, comparative proteomic study, molecular docking, molecular dynamic simulation

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(E-pub Ahead of Print)
DOI: 10.2174/1570180817999200531165148
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